Prognostic and clinicopathological significance of systemic inflammation response index in patients with hepatocellular carcinoma: a systematic review and meta-analysis

Background It is unclear whether the systemic inflammation response index (SIRI) can predict the prognosis of patients with hepatocellular carcinoma (HCC). Consequently, the present study focused on systematically identifying the relationship between SIRI and the prognosis of patients with HCC through a meta-analysis. Methods Systematic and comprehensive studies were retrieved from PubMed, Web of Science, Embase, and the Cochrane Library from their inception to August 10, 2023. The role of SIRI in predicting overall survival (OS) and progression-free survival (PFS) in HCC was determined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Odds ratios (ORs) and 95% CIs were pooled to analyze the correlations between SIRI and the clinicopathological features of HCC. Results Ten articles involving 2,439 patients were included. An elevated SIRI was significantly associated with dismal OS (HR=1.75, 95% CI=1.52–2.01, p<0.001) and inferior PFS (HR=1.66, 95% CI=1.34–2.05, p<0.001) in patients with HCC. Additionally, according to the combined results, the increased SIRI was significantly related to multiple tumor numbers (OR=1.42, 95% CI=1.09–1.85, p=0.009) and maximum tumor diameter >5 cm (OR=3.06, 95% CI=1.76–5.30, p<0.001). However, the SIRI did not show any significant relationship with sex, alpha-fetoprotein content, Child-Pugh class, or hepatitis B virus infection. Conclusion According to our results, elevated SIRI significantly predicted OS and PFS in patients with HCC. Moreover, the SIRI was significantly associated with tumor aggressiveness. Systematic review registration https://inplasy.com/inplasy-2023-9-0003/, identifier INPLASY202390003.


Introduction
Primary liver cancer ranks sixth among cancers in terms of morbidity and is the third most common cause of cancer-associated mortality worldwide (1).As estimated by GLOBCAN, 905,677 new liver cancer cases and 830,180 liver cancer-associated deaths were reported globally in 2020 (1).Hepatocellular carcinoma (HCC), the most frequent subtype of liver cancer, affects approximately 75% of patients worldwide (2).Approximately 72% of the HCC cases are reported in Asia (over 50% in China), and 10%, 7.8%, 5.1%, 4.6%, and 0.5% in Europe, Africa, North America, Latin America, and Oceania, respectively (3).In general, surgery, local thermal ablation, liver transplantation (LT), transcatheter arterial chemoembolization (TACE), and systemic therapy are the main treatments for HCC and have shown efficacy in reducing the mortality rates of HCC (4).Despite this, the long-term survival rates of patients remain unsatisfactory, and recurrence rates are high (5).Among patients with localized or metastatic HCC, the 5-year overall survival (OS) rate is < 10% (6).In addition, up to 70% of patients experience recurrence after undergoing treatment with a curative intent (6).Therefore, the identification of effective prognostic biomarkers is pivotal for risk stratification and adjunctive treatment development in patients with HCC.
Accumulating evidence suggests that immune responses and inflammation influence tumor progression and metastasis (7).

Study guideline
The present meta-analysis was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (28).Our meta-analysis protocol was registered in INPLASY (registration number: INPLASY202390003) and can be found at https://inplasy.com/inplasy-2023-9-0003/.

Ethics statement
Data in this study were extracted from publications, and, as a result, ethical approval or patient consent was waived.

Literature search
The PubMed, Web of Science, Embase, and Cochrane Library databases were comprehensively searched from their inception to August 10, 2023, using the following search terms: (systemic inflammation response index or systemic inflammatory response index) and (hepatocellular carcinoma, hepatocellular cancer, HCC, or liver cancer).A detailed search strategy for each database is provided in Supplementary Data Sheet 1.The language used in this study was English.To identify additional eligible articles, we manually searched the reference lists of each retrieved article.

Inclusion and exclusion criteria
Articles satisfying the following criteria were recruited: (1) HCC was diagnosed based on pathology or histology; (2) studies investigating the relationship between SIRI and prognosis of patients with HCC; (3) those with available or calculable hazard ratios (HRs) and 95% confidence intervals (CIs); (4) those mentioning threshold SIRI; (5) those reporting survival outcomes such as OS, disease-free survival (DFS), progression-free survival (PFS), or cancer-specific survival (CSS); and (6) English language articles.The following studies were excluded: (1) meeting abstracts, reviews, comments, letters, and case reports; (2) animal studies; and (3) those including overlapping patients.

Data extraction and quality assessment
The studies were reviewed and data were independently extracted from qualified studies by two reviewers (SZ and ZT).Any dispensaries were resolved through negotiation until a consensus was reached.The following information was collected: first author, publication year, country, study design, sample size, age, sex, study center, study period, Child-Pugh class, treatment, threshold, threshold selection method, survival outcomes, survival analysis type, follow-up, HRs, and 95%CIs for survival outcomes.If eligible studies underwent propensity score matching (PSM) analysis, the data for the entire population were extracted and analyzed to avoid selection bias.OS and PFS were defined as the primary and secondary survival outcomes, respectively.Two researchers (SZ and ZT) evaluated the literature quality using the Newcastle-Ottawa Scale (NOS) (29) and crosschecked our results.The NOS assesses literature quality from three perspectives: selection, comparability, and outcome measurement.The NOS score ranges from 0 to 9, with studies scoring ≥ 6 points considered to be of high quality.

Statistical analysis
The significance of the SIRI in predicting the OS and PFS of patients with HCC was evaluated based on the combined HRs and 95% CI.Interstudy heterogeneity was evaluated using the Higgins I 2 statistic and Cochran's Q test.The random-effects model was applied when I 2 was >50% or P was <0.1; otherwise, the fixedeffects model was used.Diverse factor-stratified subgroup analyses were conducted to identify sources of heterogeneity.The relationships between SIRI and the clinicopathological characteristics of HCC were analyzed using combined odds ratios (ORs) and 95% CIs.A sensitivity analysis was used to evaluate the consistency of the findings.Meta-regression was conducted to evaluate the effect of clinicopathological factors on the overall results.Begg's test, funnel plots, and Egger's test were used to examine possible publication bias.Stata software (version 12.0; Stata Corp., College Station, TX, USA) was used for graph generation and statistical analyses.Statistical significance was set at P<0.05.

Study selection process
As shown in Figure 1, 529 studies were identified through primary literature retrieval, and 398 records were retained following the removal of duplicates.Subsequently, 360 articles were discarded by title and abstract screening owing to their irrelevance.Then, the full texts of 38 articles were examined, and another 28 were excluded because they did not focus on SIRI (n=24) or recruited overlapping patients (n=4).Finally, the present meta-analysis recruited 10 articles involving 2,439 patients (18-27) (Figure 1; Table 1).

SIRI and OS
Six studies involving 1,598 patients (18)(19)(20)(23)(24)(25) provided data on the significance of SIRI in predicting OS in HCC.There was no obvious heterogeneity (I 2 = 0, P=0.479); therefore, we adopted a fixed-effects model.As shown in Table 2 and Figure 2, the HR was

SIRI and PFS
Altogether, eight articles comprising 2,008 patients (20-27) reported a correlation between SIRI and PFS in patients with HCC.Because of significant heterogeneity, we employed the random-effects model (I 2 = 78.8%,P<0.001; Table 3 and Figure 3).Based on the pooled results, an increased SIRI significantly predicted inferior PFS in HCC (HR=1.66,95% CI=1.34-2.05,p<0.001; Figure 3; Table 3).Forest plots of the prognostic role of SIRI for OS in patients with HCC.Subgroup analysis indicated that elevated SIRI still significantly predicted PFS in HCC, which was unaffected by country, treatment, sample size, study center, threshold, threshold selection method, or survival analysis type (Table 3).

Sensitivity analysis and meta-regression
By removing studies study-by-study, sensitivity analysis revealed that none of the studies had an effect on OS or PFS, suggesting that all results remained consistent (Figure 5).Meta- Zhang and Tang 10.3389/fimmu.2024.1291840 Frontiers in Immunology frontiersin.orgregression showed that none of the factors significantly influenced the overall results of OS and PFS (Tables 2, 3).

Publication bias
Begg's test, funnel plots, and Egger's test were used to assess potential publication bias.The funnel plot did not exhibit any significant asymmetry in the OS or PFS (Figure 6).Moreover, the results indicated no significant publication bias for OS (Begg's p=0.1 33; Egge r' s p=0.358) or PFS (Begg' s p= 0.536 ; Egger's p=0.302).

Discussion
The prognostic significance of SIRI in patients with HCC remains inconsistent.This meta-analysis collected data from 10 articles involving 2,439 patients.According to our results, elevated SIRI levels were markedly associated with shortened OS and inferior PFS in patients with HCC.Additionally, a high SIRI was significantly correlated with multiple tumor numbers and tumor size >5 cm in HCC.Publication bias tests and subgroup analyses were conducted to verify the reliability of the findings.Collectively, SIRI serves as a promising and cost-effective factor for predicting the short-and long-term prognoses of patients with HCC.To the best of our knowledge, this is the first meta-analysis to explore the potential of SIRI in predicting the prognosis of patients with HCC.SIRI was calculated using the following formula: SIRI= neutrophil count × monocyte count/lymphocyte count.Therefore, a high SIRI could be the result of increased neutrophils, increased monocytes, and/or decreased lymphocytes.Currently, the accurate predictive mechanism of SIRI in HCC prognosis remains largely unclear and can be interpreted as follows: First, neutrophils recruited to a tumor site can produce inflammatory factors, such as interleukin-1 (IL-1) and IL-6, promoting the growth and metastasis of tumor cells (7).Activated neutrophils can suppress T cell proliferation and cytotoxicity by binding PD-L1 on the neutrophil surface to PD-1 on the T cell surface (30).This may promote tumor immune evasion and malignant growth, ultimately resulting in a shorter lifespan in cancer patients (31).Second, monocytes may differentiate into tumor-associated macrophages (TAMs) (32).TAMs secrete several inflammatory factors that affect the tumor microenvironment, thereby promoting tumor occurrence, metastasis, and relapse (33).Many studies have demonstrated the presence of TAM infiltration in the HCC matrix, accelerating tumor angiogenesis, growth, metastasis, and immunosuppression (34,35).Third, lymphocytes play a critical role in cellular anti-tumor responses.Tumor-infiltrating lymphocytes (TILs) have a pivotal impact on the anticancer immune microenvironment and are involved in multiple stages of tumor progression (36).The presence of lymphocyte infiltration in tumor tissues is associated with improved therapeutic outcomes.However, when the number of lymphocytes in the tumor microenvironment decreases, anti-tumor ability decreases, resulting in immune tolerance and tumor escape (37).Taken together, a high SIRI may significantly predict the prognosis of patients with HCC.Notably, the degree of liver fibrosis may significantly affect SIRI.As these data were rarely evaluated in the included papers, they were not analyzed.However, the development of HCC in cirrhotic and non-cirrhotic livers differs significantly.Future studies are needed to investigate the prognostic value of SIRI for HCC in both cirrhotic and non-cirrhotic liver groups.Evaluating liver function is essential for determining the prognosis of HCC although the Child-Pugh score alone is not sufficient to do so.A major prognostic factor for HCC is portal hypertension, which may affect the SIRI; however, this has rarely been examined in the included studies.None of the included studies provided data on portal hypertension.Therefore, we expect future studies to evaluate the prognostic value of the SIRI under different circumstances of portal hypertension.Sarcopenia is another important prognostic factor in patients with solid tumors (38-42).Current evidence shows that sarcopenia is independently associated with a poor prognosis in various cancers (38)(39)(40)(41)(42). Previous studies have also indicated that many patients with HCC have sarcopenia (43)(44)(45).The SIRI is associated with tumor characteristics but may also be influenced by general health status, particularly sarcopenia.However, the included studies did not present data on sarcopenia.Therefore, we expect that the correlation between SIRI and sarcopenia in HCC can be investigated in future studies.
Recently, meta-analyses have been conducted to determine whether SIRI can be used to predict the prognosis of solid tumors.A meta-analysis conducted by Wang et al. found that the SIRI independently predicted the prognosis and survival status of nasopharyngeal carcinoma based on 3,187 patients (46).Another meta-analysis of 10,754 cases by Zhou et al. showed that a high SIRI was related to shorter OS and DFS/recurrence-free survival/PFS in various cancers (47).In addition, in a meta-analysis of 14 studies, Wei et al. demonstrated that the SIRI is a useful factor for predicting dismal prognostic outcomes during malignancy treatment (48).The present study identified an obvious relationship between SIRI and survival in HCC, which is in accordance with findings in other cancer types.
This study has certain limitations.First, the articles included were from Asian countries, particularly China.Although only articles in the English language were included, the applicability of our results should be noted.Second, the SIRI cut-off values differed, possibly inducing heterogeneity in the present study.Third, the sample size was relatively small.Therefore, large-scale prospective trials using standard SIRI cut-off values should be conducted for further validation.

Conclusions
In conclusion, the present study showed that elevated SIRI levels significantly predicted OS and PFS in patients with HCC.Moreover, the SIRI was significantly associated with tumor aggressiveness.The SIRI could be used as a promising prognostic index for HCC in clinical practice.

FIGURE 1 PRISMA
FIGURE 1PRISMA flowchart of the established screening strategy.

FIGURE 3 Forest 4
FIGURE 3Forest plots of the prognostic role of SIRI for PFS in patients with HCC.

TABLE 1
Baseline characteristics of included studies in this meta-analysis.

TABLE 2
Subgroups of the prognostic value of SIRI for OS in patients with HCC.

TABLE 3
Subgroups of the prognostic value of SIRI for PFS in patients with HCC.

TABLE 4
The association between SIRI and clinicopathological factors in patients with HCC. .Sensitivity analysis.(A) OS and (B) PFS.